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1.
V L Andronova L A Aleksandrova I L Karpenko Iu S Skoblov 《Antibiotiki i khimioterapii͡a》2003,48(5):3-6
It was demonstrated that several 5'-phosphonates of 4'-thio-5-ethyl-2'-deoxyuridine possessed antiviral activity in vitro and in the murine model of herpes simplex virus type 1 infection. It was shown that the derivatives after intraabdominal administration penetrated effectively into the brain tissue. The agents provided statistically significant increase of the average life span, lower virus titre in the brain and lower lethality when compared to the control group of the animals. It is emphasized that the derivatives were less toxic than the original compound. 相似文献
2.
G. V. Mikoulinskaia S. A. Taran Yu. S. Skoblov S. A. Feofanov 《Russian Journal of Bioorganic Chemistry》2013,39(6):607-618
The amino acid residues essential for the enzymatic activity of bacteriophage T5 deoxyribonucleoside monophosphate kinase were determined using a computer model of the enzyme active site. By site-directed mutagenesis, cloning, and gene expression in E. coli, a series of proteins were obtained with single substitutions of the conserved active site amino acid residues—S13A, D16N, T17N, T17S, R130K, K131E, Q134A, G137A, T138A, W150F, W150A, D170N, R172I, and E176Q. After purification by ion exchange and affine chromatography electrophoretically homogeneous preparations were obtained. The study of the enzymatic activity with natural acceptors of the phosphoryl group (dAMP, dCMP, dGMP, and dTMP) demonstrated that the substitutions of charged amino acid residues of the NMP binding domain (R130, R172, D170, and E176) caused nearly complete loss of enzymatic properties. It was found that the presence of the OH-group at position 17 was also important for the catalytic activity. On the basis of the analysis of specific activity variations we assumed that arginine residues at positions 130 and 172 were involved in the binding to the donor γ-phosphoryl and acceptor α-phosphoryl groups, as well as the aspartic acid residue at position 16 of the ATP-binding site (P-loop), in the binding to some acceptors, first of all dTMP. Disproportional changes in enzymatic activities of partially active mutants, G137A, T138A, T17N, Q134A, S13A, and D16N, toward different substrates may indicate that different amino acid residues participate in the binding to various substrates. 相似文献
3.
Aleksandrova L. A. Andronova V. L. Karpenko I. L. Skoblov Yu. S. Adani A. Galegov G. A. 《Russian Journal of Bioorganic Chemistry》2002,28(5):412-418
A number of new 5"-phosphonate derivatives of 4"-thio-5-ethyl-2"-deoxyuridine (TEDU) were synthesized. These compounds displayed a low cytotoxicity and, except for TEDU 5"-fluorophosphate, antiherpes activity similar to that of 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir) and 9-(1,3-dihydroxy-2-propoxymethyl)guanine (pencyclovir). 5"-Ethoxycarbonylphosphonate and 5"-aminocarbonylphosphonate of TEDU were also found to suppress the reproduction of herpes simplex type 1 virus, which is resistant to acyclovir. 相似文献
4.
Karpenko IL Jasko MV Andronova VL Ivanov AV Kukhanova MK Galegov GA Skoblov YS 《Nucleosides, nucleotides & nucleic acids》2003,22(3):319-328
Phosphonate derivatives of acyclovir containing phosphorous acid and ethoxycarbonylphosphonic acid residues as well as their isopropyl esters were prepared. They selectively inhibited the herpes simplex virus 1 reproduction in Vero cell culture, the efficacy of esters being 3-4 times higher than that of ACV. The hydrolysis of the synthesized compounds was studied in the PBS buffer and human blood serum. 相似文献
5.
Alexey A. Zeifman Fedor N. Novikov Victor S. Stroylov Oleg V. Stroganov Ghermes G. Chilov Alexander Y. Skoblov Anatoly I. Miroshnikov Yuri S. Skoblov 《FEBS letters》2014
2,3-Dihydroxy-quinoxaline, a small molecule that promotes ATPase catalytic activity of Herpes Simplex Virus thymidine kinase (HSV-TK), was identified by virtual screening. This compound competitively inhibited HSV-TK catalyzed phosphorylation of acyclovir with Ki = 250 μM (95% CI: 106–405 μM) and dose-dependently increased the rate of the ATP hydrolysis with KM = 112 μM (95% CI: 28–195 μM). The kinetic scheme consistent with this experimental data is proposed. 相似文献
6.
7.
Yanvarev DV Shirokova EA Astapova MV Skoblov YS 《Nucleosides, nucleotides & nucleic acids》2007,26(1):23-36
Biochemical and metabolic transformations of 3'-azido-3'-deoxythymidine 5'-choline phosphate (1) were studied using its 32P-labelled counterpart for the evaluation of possible reasons for its enhanced anti-HIV activity. An effective synthesis of 32P-labelled 1 with a specific activity >1,000 Ci/mmol was developed by esterification of 32P-phosphoric acid with choline in the presence of BrCN followed by the coupling of the resulting choline phosphate with 3'-azido-3'-deoxythymidine (AZT). Chemical and enzymatic stabilities of 1 as well as the dynamics of penetration through HL-60 cell membranes were studied at the concentrations comparable to its antiviral concentrations. The products of intracellular transformations of the studied nucleotide were identified. 相似文献
8.
V. N. Stepanenko R. S. Esipov A. I. Miroshnikov V. L. Andronova G. A. Galegov M. V. Yasko A. A. Gus’kova A. Yu. Skoblov Yu. S. Skoblov 《Russian Journal of Bioorganic Chemistry》2011,37(4):436-440
Thymidine kinase UL23 gene (EC 2.7.1.145) from the L2 acyclovir-sensitive strain of herpes simplex virus type 1 was cloned and expressed in E. coli. The enzyme was purified by chromatography to the purity of 90% according to PAG electrophoresis data. The Michaelis constants
for the reactions with thymidine and acyclovir were determined. The enzyme was found to phosphorylate modified nucleosides,
particularly 3′-deoxythymidine, 3′-deoxy-2′,3′-didehydrothymidine, 2′,3′-dideoxycytidine, 9-[(hydroxyethyl)methyl]guanine,
E-5-(2-bromovinyl-2′-deoxyuridine, 9-(1,3-dihydroxy-2-propoxymethyl)guanine, 2′,3′-dideoxydehydrothymidine, β-L-2′,3′-dideoxy-3′-thiacytidine, and 3′-fluoro-3′-deoxythymidine. Some properties of the purified enzyme were compared with
those of thymidine kinases of other herpes simplex virus strains. It was shown that acyclovir H-phosphonate inhibited the
enzyme. 相似文献
9.
Skoblov AIu Ias'ko MV Murabuldaev AM Kukhanova MK Skoblov IuS 《Bioorganicheskaia khimiia》2005,31(6):623-626
The total fraction of aminoacyl-tRNA synthases from Escherichia coli has been shown to catalyze the synthesis of the bis(5'-nucleosidyl) oligophosphates Ap4AZT, Ap4d4T, Ap43TC, and Ap4ACV, as well as Ap3AZT and Ap3d4T, from [alpha-32P]ATP and the corresponding nucleoside-5'-tri(or di)phosphate. The resulting compounds, characterized by HPLC, are resistant to alkaline phosphatase. Ap4AZT, Ap4d4T, and Ap43TC are formed with approximately equal efficiency, whereas the efficiencies of the synthesis of Ap4ACV, Ap3AZT, and Ap3d4T are three- to fivefold lower. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2005, vol. 31, no. 6; see also http://www.maik.ru. 相似文献
10.
Aleksandrov AN Skoblov IuS Skoblov MIu Shibanova ED Baĭramashvili DI Miroshnikov AI 《Bioorganicheskaia khimiia》2005,31(1):73-76
A semiquantitative assay of DNA impurities in preparations of human recombinant insulin is described. The assay is based on the detection of a fragment of the ampicillin-resistant gene within the producer strain DNA by PCR. The analysis of PCR products of the studied preparations and PCR products containing known amounts of E. coli total DNA enabled a quantitative determination of the producer strain DNA content in the preparations under study. The sensitivity of the method is 7 pg of E. coli DNA per 10 microg of human recombinant insulin. The high sensitivity of the method allows us to recommend it for the quantitative determination of DNA content in recombinant preparations that do not inhibit PCR. 相似文献